Lung Transplantation Clinical Trial
Bronchiolitis obliterable syndrome (BOS) is the most common cause of death in long-term
survivors after lung transplantation and refractory to most interventions. Many risk factor
for BOS were identified in previous studies such as acute cellular rejection, lymphocytic
bronchiolitis, cytomegalovirus (CMV) and non-CMV respiratory infections, injury to the
allograft or airways, Primary graft dysfunction, HLA mismatching, and organizing pneumonia.
(Belperio JA. et al.). Neutrophils and their released products may be involved in the
development of BOS. Neutrophilia was repeatedly observed in the bronchoalveolar lavage fluid
of patients after lung transplantation. In addition, infiltration of neutrophils into the
bronchial epithelium has been detected in patients with higher degrees of active airway
damage. Neutrophils are capable of causing severe damage to the lung tissue by releasing
toxic proteases and reactive oxygen species if not counterbalanced by the antiprotease/
antioxidant screen of the lung. Based on this background, a causal relationship between
neutrophilia and the development of BOS has been proposed. (Hirsch J. et al.) Detection of
unopposed Neutrophile elastase (NE) activity in BAL appears to correlate with poor outcome
due to refractory BOS. Unopposed NE in these subjects may not only serve as a marker of
evolving graft dysfunction but also participate in damaging the airways of the allograft and
inhibit adequate bacterial clearance. Prevention of neutrophil sequestration or inhibition
of NE may prevent or attenuate airway damage and improve bacterial clearance mechanisms.
(Nutley D et al.) These data demonstrate the importance of neutrophils and unopposed NE in
the pathogenesis of BOS and call for new approach to prevent or modulate BOS targeting this
mechanism.
AAT is the main inhibitor of neutrophil elastase in the lower airways and patients with AAT
deficiency have low concentrations of the protein in this region of the lung. This explains
the proteinase/antiproteinase theory of the development of emphysema in deficient patients
in which the amount of elastase released in the lung exceeds the amount of AAT. The net
result is persistence of elastase activity leading to lung destruction and the pathological
changes of emphysema. (Abusriwil H. et al.) The administration of the AAT is to address
proteinase/antiproteinase imbalance.
Administration of AAT will help to prevent further destruction of the lung architecture and
reduce the inflammatory dysregulation that causes pulmonary dysfunction. It is expected that
by attacking a specific and previously untreated key component part of the
pathophysiological cycle of BOS, AAT therapy would decrease the prevalence of BOS in lung
transplant recipients and prolong life expectancy of these patients.
Status | Not yet recruiting |
Enrollment | 40 |
Est. completion date | September 2013 |
Est. primary completion date | September 2012 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 70 Years |
Eligibility |
Inclusion Criteria:• Patients aged =18 years - Signature of informed consent - Lung transplant recipient in the past 6 months. - Stable concomitant therapy >2 weeks prior to visit 1 - Non-tobacco user of any kind - No significant abnormalities in serum hematology, serum chemistry to the Principal Investigator's judgment((Hg>8g/dL ,Creatinine<2mg/dl,Liver enzymes<3*ULN) - Non-pregnant, non-lactating female subjects, whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator, or who are more than 5 years post-menopausal or surgically sterilized or whose way-of-life excludes sexual activity. - Sexually active female subjects of child-bearing potential, as well as male subjects, must use a medically acceptable effective contraceptive method (for male - method such us condoms; for female - methods such as oral contraceptive medication used for at least two weeks before study start, or a combination of any two of the following: diaphragm, cervical cap, condom or spermicide), before study start and throughout the entire duration of the study. Exclusion Criteria:• Diagnosis of BOS with according to Estenne M. et al. - Hospitalization within 1 month before study entry, not due to an airway disease - Severe liver cirrhosis with ascites - Hypersplenism - Grade III/IV esophageal varices; - Active pulmonary exacerbation within the 4 weeks prior to screening - History of massive hemoptysis: greater than 200 cc in a 24 hour period - Pregnancy or breastfeeding - Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol. - Fever at the time of the start of first (day #1) inhalation (oral temperature >38ºC) - Evidence of uncontrolled hypertension - Pulse >120/min (prior to study drug administration) - Any serious malignancy except for basal and squamous (scaly or plate-like) cell skin cancer within the previous 3 years prior to study start - Receipt of exogenous AAT within the last 6 months - Previous enrolment in this study (subject can not be enrolled twice into the study) - Evidence of congestive heart failure or other clinically significant cardiovascular conditions: myocardial infarction during the last year, arrhythmia requiring drug treatment during the last year, uncontrolled hypertension - Current smoker (someone who has smoked within 4 weeks prior to screening) - Subjects with an additional clinically significant inter-current illness (beside lung disease) (e.g., cardiac, hepatic, renal, endocrine, respiratory, neurological, hematological, neoplastic, immunological and skeletal) that the investigator determines that it could interfere with the safety or other assessments of this study - Any evidence of alcohol abuse or history of abuse of illegal and/or legally prescribed drugs such as barbiturates, benzodiazepines, amphetamines, cocaine, opioids, and cannabinoids - Being a sexually active female of child-bearing age without adequate contraception - Any other factor that, in the opinion of the investigator, would prevent the subject form complying with the requirements of the protocol |
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
n/a |
Lead Sponsor | Collaborator |
---|---|
Rabin Medical Center |
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Clinical diagnosis of BOS according to Estenne M. et al Treatment of lung transplant recipients to prevent BOS Clinical diagnosis of BOS according to Estenne M. et al. Adverse events and conc | Adverse events and concomitant medication recording and follow up. Safety/tolerability parameters at baseline (Day #1) will be compared with values generated at the following visits every 6 weeks (+/- 10 days). At all visits, AEs and concomitant medications will be recorded. Additionally, the study coordinator will check occurrence of AE and concomitant medications by a telephone visit |
12 Month | Yes |
Secondary | Change in lung function test | Change in lung function FEV%, FEV1, FVC Baseline (Day #1) values of FEV1 and FVC (and FEV%) will be compared to the following visits every 6 weeks (+/- 10 days). Incidence of Acute cellular rejection. Incidence of respiratory infection leading to antibiotics administration according to the decision of the investigator. |
12 month | Yes |
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